The incidence of the Sudden Infant Death Syndrome (SIDS) has decreased substantially in the United States and elsewhere as a result of educational campaigns favoring the supine posture for sleeping infants. Despite this success, SIDS remains a major contributor to infant mortality. Further progress in the prevention of SIDS is likely to require improved understanding of its pathogenesis. The laryngeal chemoreflex (LCR)-apnea and swallowing in response to intralaryngeal water, milk or other fluids-is more prominent in newborn animals and human infants than in adults and, therefore, has long been suspected as a cause of some cases of SIDS. We found during the past four years that the LCR is greatly exaggerated in neonatal piglets that are warmed 1- 3 0C above their normal body temperatures. This effect of hyperthermia is reversible by body cooling and can be repeated several times in the same animal. The laryngeal water receptors are not influenced by temperature changes in this range, but locally warming the medulla in the region of the nucleus of the solitary tract (NTS), where afferents from the larynx make their synaptic connections with neurons that control breathing and swallowing, reversibly exaggerates the LCR, strongly implying a medullary site of action for the previously demonstrated effect of whole body warming on the LCR. The influence of medullary temperature on the duration and intensity of the LCR is a striking new finding, which is of compelling importance in the pathogenesis of SIDS. In this renewal application, we will study the mechanism of this temperature effect and place it in the context of other findings related to SIDS. We will study decerebrate piglets to determine (1) whether the exaggeration of laryngeal apnea by hyperthermia is due to excessive activity of GABA, the major inhibitory neurotransmitter of the central nervous system, (2) whether the thermal exaggeration of laryngeal apnea is influenced by manipulation in the medulla of neurotransmitters whose receptors have been shown to be deficient in SIDS infants, (3) the behavior of temperature sensitive neurons in the NTS during elicitation of laryngeal apnea at normal and elevated body temperatures and (4) whether TRPV1 channels are involved in the thermal exaggeration of laryngeal apnea.. We will also study intact, chronically instrumented piglets during wakefulness, NREM and REM sleep to determine the combined influence on the LCR of hyperthermia and manipulation of central nervous system neurotransmitters under more natural conditions. The results of these experiments will provide insight about the interactions of temperature and neurotransmitters on the LCR and may lead to rational preventive therapies for infants in groups that are at high risk for SIDS. 7. PUBLIC HEALTH RELEVANCE: Sudden Infant Death Syndrome (SIDS) - the unexpected death of an apparently healthy baby, usually during sleep - is a major cause of infant mortality and a devastating event for the baby's parents. One suspected mechanism of SIDS is that stomach contents, regurgitated into the larynx, trigger a powerful reflex that stops breathing and leads to death from oxygen lack. We will examine this reflex and its enhancement by increased body temperature in neonatal piglets in an effort to find tests for SIDS susceptibility and preventive treatments for infants identified as being at risk.